Innate Immunity Flashcards
barriers against disease
skin, mucous, lysozomes, pH, sebum, etc
humoral defense against disease
bacteriocidal substances, ROI, complement, APP, transport proteins, coagulation proteins, interferon
cellular defense against immunity
blood cells (neutrophils, eosinophils, basophils, monocytes, NK cells) tissue: macrophages, dendritic cells, mast cells
skin and mucous membranes contain
sebaceous glands and sebum which inhibit microbe growth with a low pH or with antimicrobial stubastances and cilia
inflammation is triggered by
injury or invasion
inflammation functions to
protect tissues but causes damage and disease too
normally the damage is repaired, but inflammation can become chronic
inflammatory mediators result from vasoactice mediators such as
prostaglandins, leukotrienes and histamine from mast cells
bradykinin from kinin system
microbes/injury trigger tissue/sentinal cells
mast cells, macrophages, dendritic cells
signs/systems of inflammation and infection
blood supply increases, causes redness and warmth
BV are permeable, so swelling happens
immune cells are recruited and kill pathogens, causing tissue debris
WBC attack and release substances to continue inflammation
inflammatory mediators can cause pain by nerve stimulation
body reacts with chills, fever, muscle aches
innate responses are often sufficient to
prevent infection in tissues and blood, but might not be enough to overcome large numbers of microorganisms
fever is caused by
TNF, IL1, IL6 from macrophages in response to pathogens
controlled by hypothalamus
innate immune cells can tell
self from nonself using PAMPs
PAMPs (on the surface of the pathogen!)
pathogen-associated molecular patterns
unique to specific classes of pathogens-molecular patterns
cannot be altered, supressed or hidden from the surface
not structurally similar to self-antigens
PAMPs include
porins lipoproteins lipopolysacharadies teichoic acid mannoproteins b-glycan lipoarabinomannan
PRRs
example is mannose receptor
bacteria, fungi, and viruses need a glycan with mannose tails
no human cells have glycans with terminal mannose
PRRs are coded in
germ line
undergo non clonal distribution meaning that all cells have receptors with idenitical specificities
Toll like receptros
pair with eachother and recognize pathogens
Extracellular TLRs
1 2 4 5 6
intracellular TLRs
3
7
8
9
TLRs recognize
PAMPs and activate inflammation
endosomal TLRs
located in endosomes into which microbes are ingested
respond only to nucleic acids
TLR signals activate
transcription factors that stimulate expression of cytokines and other mediators for inflammation
nuclear factro kB
NF-KB one of the most important TF activated by TLRs
promotes expression of various cytokines and adhesion molecules (MOST important for inflammation)
Interferon regualtory factors
another inportant Tf
stimualtes production of antiviral cytokines IFNa/b
aka type I interferons
bacteria
TLR 1 2 4 5 9
viruses
3
7
8
9
Fungi
2
6
MyD88
adaptor protein
TRIF
adaptor protein
IRF
a transcription factor
IRAK
kinase
TRAF6
adaptor protein
TLR4 dependent cell activation
TLR4, MD2, CD14 and LPS is assebled on pathogen surface
MyD88 binds TLR4 and activates IRAK4 to p1 TRAF6 leading to activation of IKK
IKKp IxB causing its degradation and release of NFkB to go to nucleus
NFkB activates genes for inflammatory cytokines made in cytoplasm and secreted via ER
Pamps activate complexes called
inflamasomes containing NLRs
NLRs act as
scaffolding proteins
assemble signaling platforms that trigger activation of NF-kB and MAPK
best NLR is
NLRP3
inflammasomes activate
protease caspase 2
main function of caspase 1 is to make
IL-1B and IL-18 which drive inflammation
these are produced in the inflammasome
DAMPs
damage associated molecular patterns
danger molecules released in damaged or dying vells
while PAMPs are from pathogens, DAMPs are from
cell/ecm
both trigger similar types of inducers and same types of sensors leading to same mediators
DAMPs released a lot in ___ and little in ___
necrosis; apoptosis
DAMPs include
HGMB1
uric acid
HSPs
when these are released from a necrotic cells trigger TLR 2, 4 and NLRP 3 which trigger NFkB
loss of self tolerance leads to
development of autoimmune diseases
DAMPs play a role in development of the loss of self-antigen recognition
PRR-triggered response: fMet
Fmet is part of prokaryotes but not eukaryotes
fMet is typical PAMP
neutrophils and macrophages see fMEt to distinguish self from nonself
formyl peptide receptor PRR (GPCR) involved in chemotaxis
phagocytes bind to bacterial proteins starting with fMet and use them to inititate phagocytosis
macrophages respond to
danger signals-DAMPs and PAMPs
mcarophages regulate exravasation of
blood into tissue
machrophages degrade by
phagocytosis and do tissue repair
macrophages play a role in inflammation by
cytokines and chemokines ROI NO prostaglandins defensins
macrophages present antigens to
effetor t cells
macrophages immunomodulate meaning
maintain homeostasis in tissue
mast cells express receptros for
many DAMPs and PAMPs
mast cells can amplify or supress
innate and acquired immune repsonses
mast cells secrete
proinflammatory
antiinflammatory
immunosupressive products
mast cells are located in areas exposed to
external environment
regualte vascular permeability and recruitment of blood cells
can modulate effector cells through release of mediators
cytokines
small proteins secreted by cells
mediate inflammation, immunity, and hematopoeisis
can be endocrine, paracrin and autocrine
cytokines in the innate immunity have two different classes
proinflammatory
antiinflammatory
chemokines
small protein chemoattractants important for traffickin immune cells
ANTIINFLAMMATORY CYTOKINES
IL 10 (only true antiinflammatory) TGF-B
Inflammatory cytokines
TNFa
IL 1
IL6
IL8
activation of the complement system result in
procution of several different polypeptide cleavage fragments involved in functions of inflammation
all complement pathway prodcuts lead to
C3b which activates C5 which forms the MAC which puts holes in plasma membranes and kills pathogems
lipoppolysaccharide is the most
potent activator on macrpphages for forming inflammatory mediators
classic complement pathway initiation
binding of one IgM or two IgG on microbial surface
classic complement pathway c1 complex binds to
IgM or 2xIgG
becomes activated
activated C1 cleaves
C2 and C4 (one activated C1 molecule can cleave many C2 and C4 molecules)
makes C4b and C4b
makes C2b and C2a
C4 covalently attaches to
microbial surfaces
C2a binds to the
surface attached C4b thus forming
C4bC2a=C3 convertase
C3 convertase cleaves
Cd3 into C3a and C3b
C3b deposits on
surface of bacteria
surface bound C3b is an
opsonin and increases phagocytosis by phagocytic cells
C3b can form a complex with
C3 convertase to make the C5 convertase (c4bc2a3b)
C5 convertase cleaves C5 into
C5a and C5b
C5b initiates
MAC (lytic pathway)
C5a is teh
anaphylactoxin
MAC
contains C5b, C6, C7, C8 togeher with many C9
leads to cell lysis
APP
CRP
mannose binding protien
a-acid glycoprotein
serum amyloid P component
CRP and MBP
fix complement, opsonize
mast cell receptors
IgE, Ag
PAMPs
cytokine/chemokine receptors
C3a, C5a complement
temperature/pressure
cell to cell contact
mast cell effector molecules
histamine proteases serotinin heparin cytokines IL4,TNF
prostaglandins
leukotriene
cytokines
chemokines
interferon gamma a and b activates
macrophages
inteface between innate and adaptive
macrophages express all OTHER cytokines
cytokines that produce fever
6, 1b, TNF-a
IL8
chemotactic factor, recruites cells to infection (T, basophils, neutrophils)
IL12
activates NK cells, induces CD4 T cells into Th1 cells
without IL 12, goes toward
B cell/immunigloblin
IL12 also acts on NK and T cells to make
IFNy which activates macrophages
IL6 generates
APP
sicknes behaviour syndrome
due to TNF-a, IL1, IL6
rolling
neutrophils come into contact with endothelial cells of blood capillaries and interact with surface adhesion molecules
TNFa, IL1, mast cells and macrophages induce activation of endothelial cells which will increase expression of
P selectins and E selectins which will bind to their ligands on neutrophils (4 steps)
4 steps of binding neutrophils to selectins
tethering: neutrophils slow down and roll on endotheliuam, mediated by ligand binding
tight binding: integrins on neutrophils and ligands on endothelial cells
diapedesis: transmigration through endothelium
chemotaxis: IL8 controls migrations of neutrophols to inflammatory sites of tissues
LGA1 and VLA4 are the integrins on the
neutrophils and monocytes in a low affinity state
while rolling, chemokine on endothelial cell can bind to receptor neutrophils
this binding activates LFA1 and VLA4 to increase affinity and binding with ICAm and VCAM
monocyte rolling
similar in steps 1-3 as neutrophils
monoyte chemoattractant protein is the most important chemokine that regualtes migration and infiltration of monocutes
matureation of monocute into macrophage is controlled by cytokine microenvironemnt
classically activated macrophages
m1
induced by TLR and cytokines especially IFNy and are microbicidal and proinflammatory
alternatively activated macrophages
M2 indcued by IL4 and IL!3
important in tissue repair and fibrosis
oxygen dependent intracellular killing is a byproduct of teh
respiratory burst taht accompanies phagocytosis
events of the respiratory burst
oxygen consumption increased
superoxide anion produced converted to H202 by superoxide dismutase
hydrogen peroxide is broken down by catalase
singlet ocygen made
hydroxyl radicals made
myeloperoxidase (toxic peroxidation)
hypochlorite made (antimicrobial)
antiviral innate immune response is mediated by
type I interferons (a/B) which block viral replication in teh host cell
NK cells which kill virus infected cells
type I IFNs induce expression of proteins that interfere with
viral replcaition to limit spread of virus
inteferon regulates PKR wich blocks viral RNA translation
IFNs activate nuclease ribonuclease L to degrade viral RNA
activate NK cells to kill infected cells
NK cells recognize ligands
on infected cells or cells undergoing other types of stress
NK cells kill infected/stressed cells
NK cell eliminate reservoirs of infection by killing of host cells and releasing intracellular pathogens for phagocytosis
NK cells secrete
IFNy type II
most powerful activator of macrophages to kill phagocutozed microbes
NK cells have activating receptors that are called
KIR (killer cell Ig like receptors) that recognize stress molecules like MICA and MICB on surface of abn. cells
trigger PTKs
NK cells have inhibiting receptors that recognize
inhibitory receptors called class I MHC and activate PTP to inihibit activation (KIR binds to this as well to inhbit)
insufficient KIR-MHC I binding occurs then the NK cell will
kill the target cell
if KIRs bind to the MHC I suffiencently, host cells is
not killed
NK cells kill infected cells with
perforins to make holes
granzymes to activate apoptosis
macrohage to eat dying cells
somce cells have resistance to innate defense mechanisms like
phagocytic resistance
ROS resistance
complement resistance
anitmicrobial peptide antibiotics resistance
T cells need two signals to activate
signal one: binding of antigen
signal two: costimulatory molex molecues from APC
extra signals from cytokines
innate immunity indirectly controsl
ab-mediated responses of adaptove immunity (becasue innate activates B and T’s are needed for B’s which make Ab)
linking innate and adaptive
PRRs activated and mature APC
APC presented to naive T cells
secreted cytokines assist in the development and maturation of T cells
